tbuckley/cabot-search huggingface dataset:
miR-223 Exerts Translational Control of Proatherogenic Genes in Macrophages
Authors: My-Anh Nguyen, Huy-Dung Hoang, Adil Rasheed, Anne-Claire Duchez, Hailey Wyatt, Mary Lynn Cottee, Tyson E. Graber, Leah Susser, Sabrina Robichaud, İbrahim Berber, Michele Geoffrion, Mireille Ouimet, Hilal Kazan, Lars Maegdefessel, Erin E. Mulvihill, Tommy Alain, Katey J. Rayner
Journal: Circulation Research (2022)

A significant burden of atherosclerotic disease is driven by inflammation. Recently, microRNAs (miRNAs) have emerged as important factors driving and protecting from atherosclerosis. miR-223 regulates cholesterol metabolism and inflammation via targeting both cholesterol biosynthesis pathway and NFkB signaling pathways; however, its role in atherosclerosis has not been investigated. We hypothesize that miR-223 globally regulates core inflammatory pathways in macrophages in response to inflammatory and atherogenic stimuli thus limiting the progression of atherosclerosis.Loss of miR-223 in macrophages decreases Abca1 gene and protein expression as well as cholesterol efflux to apoA1 (Apolipoprotein A1) and enhances proinflammatory gene expression. In contrast, overexpression of miR-223 promotes the efflux of cholesterol and macrophage polarization toward an anti-inflammatory phenotype. These beneficial effects of miR-223 are dependent on its target gene, the transcription factor Sp3. Consistent with the antiatherogenic effects of miR-223 in vitro, mice receiving miR223-/- bone marrow exhibit increased plaque size, lipid content, and circulating inflammatory cytokines (ie, IL-1β). Deficiency of miR-223 in bone marrow-derived cells also results in an increase in circulating pro-atherogenic cells (total monocytes and neutrophils) compared with control mice. Furthermore, the expression of miR-223 target gene (Sp3) and pro-inflammatory marker (Il-6) are enhanced whereas the expression of Abca1 and anti-inflammatory marker (Retnla) are reduced in aortic arches from mice lacking miR-223 in bone marrow-derived cells. In mice fed a high-cholesterol diet and in humans with unstable carotid atherosclerosis, the expression of miR-223 is increased. To further understand the molecular mechanisms underlying the effect of miR-223 on atherosclerosis in vivo, we characterized global RNA translation profile of macrophages isolated from mice receiving wild-type or miR223-/- bone marrow. Using ribosome profiling, we reveal a notable upregulation of inflammatory signaling and lipid metabolism at the translation level but less significant at the transcription level. Analysis of upregulated genes at the translation level reveal an enrichment of miR-223-binding sites, confirming that miR-223 exerts significant changes in target genes in atherogenic macrophages via altering their translation.Our study demonstrates that miR-223 can protect against atherosclerosis by acting as a global regulator of RNA translation of cholesterol efflux and inflammation pathways.
Dendritic cells can prime anti-tumor CD8+ T cell responses through major histocompatibility complex cross-dressing
Authors: Brendan W. MacNabb, Xiufen Chen, Sravya Tumuluru, James Godfrey, Darshan N. Kasal, Jovian Yu, Marlieke L.M. Jongsma, Robbert M. Spaapen, Douglas E. Kline, Justin Kline
Journal: Immunity (2022)
Revisiting the role of <i>Akkermansia muciniphila</i> as a therapeutic bacterium
Authors: Jiyeon Si, Hyena Kang, Hyun Ju You, GwangPyo Ko
Journal: Gut Microbes (2022)

Despite a short history since its first isolation, Akkermansia muciniphila has been extensively studied in relation to its effects on human metabolism. A recent human intervention study also demonstrated that the bacterium is safe to use for therapeutic purposes. The best-known effects of A. muciniphila in human health and disease relate to its ability to strengthen gut integrity, modulate insulin resistance, and protect the host from metabolic inflammation. A further molecular mechanism, induction of GLP-1 secretion through ICAM-2 receptor, was recently discovered with the identification of a new bacterial protein produced by A. muciniphila. However, other studies have suggested a detrimental role for A. muciniphila in specific host immune settings. Here, we evaluate the molecular, mechanistic effects of A. muciniphila in host health and suggest some of the missing links to be connected before the organism should be considered as a next-generation biotherapeutic agent.
Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease
Authors: Ping Bai, Prasenjit Mondal, Frederick A. Bagdasarian, Nisha Rani, Yan Liu, Ashley Gomm, Darcy R. Tocci, Se Hoon Choi, Hsiao-Ying Wey, Rudolph E. Tanzi, Can Zhang, Changning Wang
Journal: Acta Pharmaceutica Sinica B (2022)

Although the epigenetic regulatory protein histone deacetylase 6 (HDAC6) has been recently implicated in the etiology of Alzheimer's disease (AD), little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD. Here, we performed positron emission tomography (PET) imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD. We first developed [18F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6. PET studies of [18F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals, with more pronounced changes identified in the cortex and hippocampus. The translatability of this radiotracer for AD in a potential human use was supported by additional studies, including similar uptake profiles in non-human primates, an increase of HDAC6 in AD-related human postmortem hippocampal tissues by Western blotting protein analysis, and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals. Collectively, our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology.
Gender as a Risk Factor for Cardiovascular Disease in type 2 Diabetes-Sudan
Authors: Nahla Ahmed Mohammed Abderahman
Journal: Clinical Cardiology and Cardiovascular Interventions (2022)

OBJECTIVES: Researchers intended to see if there was a link between gender and an increased risk of dyslipidemia and cardiovascular disease (CVD) in Sudanese people with type 2 diabetes mellitus (T2DM) by measuring fasting plasma glucose (FPG), glycated hemoglobin (HbA1C) and lipid profiles as well as blood pressure. MATERIALS AND METHOD: During the period of April 2012 and March 2013, a case-control study was conducted in Central Sudan. The study involved 300 people who met the inclusion criteria, who were divided equally into diabetes, diabetic hypertension, and non-diabetic non hypertensive (NDNH) groups to estimate FPG, HbA1C, and lipid profile levels (TC, HDL-C, LDL-C, and TG). A15, a random access auto-analyzer bio system, was used to analyze the samples. A questionnaire was completed, which included personal information, anthropometric and biochemical measurements. After each respondent gave verbal consent, venous blood was drawn after an overnight fast. The statistical analysis was done with the help of a statistical software for social sciences (SPSS version 16, Chicago, IL, USA). RESULT: In the women's group, statistically significant differences in anthropometric measurements (WC =0.017, BMI =0.004, SBP &lt;0.0001, DBP=0.029) and biochemical measurements (FPG &lt;0.0001, HbA1C =0.007, HDL-C=0.027) were discovered when the means were compared. When the mean HDL-C values of diabetic and diabetic hypertensive women were compared, there was a significant rise of 0.029. Men, on the other hand, had statistically significant disparities in anthropometric parameters, with WC=0.001, BMI &lt;0.0001, and SBP &lt;0.0001. FPG showed a significant increase of &lt;0.0001, whereas HbA1C mean in diabetes and diabetic hypertensive patients showed poor management with no significant increase (0.615). HDL-C had a modestly high mean (0.089), while DBP had a non-significant increase (0.172). CONCLUSION: Diabetic and diabetic hypertensive women were at increased risk of dyslipidemia and CVD.
Genome Assembly and Population Resequencing Reveal the Geographical Divergence of Shanmei (<i>Rubus Corchorifolius</i>)
Authors: Yinqing Yang, Kang Zhang, Ya Xiao, Lingkui Zhang, Yile Huang, Xing Li, Shumin Chen, Yansong Peng, Shuhua Yang, Yongbo Liu, Feng Cheng
Journal: Genomics Proteomics & Bioinformatics (2022)

Rubus corchorifolius (Shanmei or mountain berry, 2n = 14) is widely distributed in China, and its fruits possess high nutritional and medicinal values. Here, we reported a high-quality chromosome-scale genome assembly of Shanmei, with contig size of 215.69 Mb and 26,696 genes. Genome comparison among Rosaceae species showed that Shanmei and Fupenzi (Rubus chingii Hu) were most closely related, followed by blackberry (Rubus occidentalis), and that environmental adaptation-related genes were expanded in the Shanmei genome. Further resequencing of 101 samples of Shanmei collected from four regions in the provinces of Yunnan, Hunan, Jiangxi, and Sichuan in China revealed that among these samples, the Hunan population of Shanmei possessed the highest diversity and represented the more ancestral population. Moreover, the Yunnan population underwent strong selection based on the nucleotide diversity, linkage disequilibrium, and historical effective population size analyses. Furthermore, genes from candidate genomic regions that showed strong divergence were significantly enriched in the flavonoid biosynthesis and plant hormone signal transduction pathways, indicating the genetic basis of adaptation of Shanmei to the local environment. The high-quality assembled genome and the variome dataset of Shanmei provide valuable resources for breeding applications and for elucidating the genome evolution and ecological adaptation of Rubus species.
Association Between Smoking History and Overall Survival in Patients Receiving Pembrolizumab for First-Line Treatment of Advanced Non–Small Cell Lung Cancer
Authors: Sanjay Popat, Stephen V. Liu, Nicolas Scheuer, Alind Gupta, Grace G. Hsu, Sreeram V. Ramagopalan, Frank Griesinger, Vivek Subbiah
Journal: JAMA Network Open (2022)

<h3>Importance</h3> There is a need to tailor treatments to patients who are most likely to derive the greatest benefit from them to improve patient outcomes and enhance cost-effectiveness of cancer therapies. <h3>Objective</h3> To compare overall survival (OS) between patients with a current or former history of smoking with patients who never smoked and initiated pembrolizumab monotherapy as first-line (1L) treatment for advanced non–small lung cancer (NSCLC). <h3>Design, Setting, and Participants</h3> This retrospective cohort study compared patients diagnosed with advanced NSCLC aged 18 or higher selected from a nationwide real-world database originating from more than 280 US cancer clinics. The study inclusion period was from January 1, 2011, to October 1, 2019. <h3>Exposures</h3> Smoking status at the time of NSCLC diagnosis. <h3>Main Outcomes and Measures</h3> OS measured from initiation of 1L pembrolizumab monotherapy. <h3>Results</h3> In this retrospective cohort study, a total of 1166 patients (median [IQR] age, 72.9 [15.3] years; 581 [49.8%] men and 585 [50.2%] women) were assessed in the primary analysis, including 91 patients [7.8%] with no history of smoking (ie, never-smokers) and 1075 patients [92.2%] who currently or formerly smoked (ie, ever-smokers). Compared with ever-smokers, never-smokers were older (median age [IQR] of 78.2 [12.0] vs 72.7 [15.5] years), more likely to be female (61 [67.0%] vs 524 [48.7%]) and to have been diagnosed with nonsquamous tumor histology (70 [76.9%] vs 738 [68.7%]). After adjustment for baseline covariates, ever-smokers who initiated 1L pembrolizumab had significantly prolonged OS compared to never-smokers (median OS: 12.8 [10.9-14.6] vs 6.5 [3.3-13.8] months; hazard ratio (HR): 0.69 [95% CI, 0.50-0.95]). This trend was observed across all sensitivity analyses for the 1L pembrolizumab cohort, but not for initiators of 1L platinum chemotherapy, for which ever-smokers showed significantly shorter OS compared with never-smokers (HR, 1.2 [95% CI, 1.07-1.33]). <h3>Conclusions and Relevance</h3> In patients with advanced NSCLC who received 1L pembrolizumab monotherapy in routine clinical practices in the US, patients who reported a current or former history of smoking at the time of diagnosis had consistently longer OS than never-smokers. This finding suggests that in never-smoking advanced NSCLC, 1L pembrolizumab monotherapy may not be the optimal therapy selection, and genomic testing for potential genomically matched therapies should be prioritized over pembrolizumab in never-smokers.
Risk of cardiovascular events in patients having had acute calcium pyrophosphate crystal arthritis
Authors: Sara K Tedeschi, Weixing Huang, Kazuki Yoshida, Daniel H Solomon
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Calcium pyrophosphate deposition (CPPD) disease, broadly defined, has been associated with increased risk of cardiovascular (CV) events. We investigated risk of CV events in patients with acute CPP crystal arthritis, the acute manifestation of CPPD. Methods Cohort study using Mass General Brigham electronic health record (EHR) data, 1991–2017. Patients with acute CPP crystal arthritis were identified using a published machine learning algorithm with positive predictive value 81%. Comparators were matched on year of EHR entry and index date of patients with acute CPP crystal arthritis (first positive synovial fluid CPP result or mention of ‘pseudogout’, or matched encounter). Major adverse cardiovascular event (MACE) was a composite of non-fatal CV event (myocardial infarction, acute coronary syndrome, coronary revascularisation, stroke) and death. We estimated incidence rates (IRs) and adjusted hazard ratios for MACE, non-fatal CV event and death, allowing for differential estimates during years 0–2 and 2–10. Sensitivity analyses included: (1) patients with acute CPP crystal arthritis diagnosed during outpatient visits, (2) patients with linked Medicare data, 2007–2016 and (3)patients matched on number of CV risk factors. Results We matched 1200 acute CPP crystal arthritis patients to 3810 comparators. IR for MACE in years 0–2 was 91/1000 person-years (p-y) in acute CPP crystal arthritis and 59/1000 p-y in comparators. In years 2–10, IR for MACE was 58/1000 p-y in acute CPP crystal arthritis and 53/1000 p-y in comparators. Acute CPP crystal arthritis was significantly associated with increased risk for MACE in years 0–2 (HR 1.32, 95% CI 1.01 to 1.73) and non-fatal CV event in years 0–2 (HR 1.92, 95% CI 1.12 to 3.28) and years 2–10 (HR 2.18, 95% CI 1.27 to 3.75), but not death. Results of sensitivity analyses were similar to the primary analysis; in the outpatient-only analysis, risk of non-fatal CVE was significantly elevated in years 2–10 but not in years 0–2. Conclusions Acute CPP crystal arthritis was significantly associated with elevated short and long-term risk for non-fatal CV event.
Deficiency of PSRC1 accelerates atherosclerosis by increasing TMAO production via manipulating gut microbiota and flavin monooxygenase 3
Authors: Tiantian Luo, Zhigang Guo, Dan Liu, Zhongzhou Guo, Qiao Wu, Qinxian Li, Rongzhan Lin, Peier Chen, Caiwen Ou, Minsheng Chen
Journal: Gut Microbes (2022)

Maladaptive inflammatory and immune responses are responsible for intestinal barrier integrity and function dysregulation. Proline/serine-rich coiled-coil protein 1 (PSRC1) critically contributes to the immune system, but direct data on the gut microbiota and the microbial metabolite trimethylamine N-oxide (TMAO) are lacking. Here, we investigated the impact of PSRC1 deletion on TMAO generation and atherosclerosis. We first found that PSRC1 deletion in apoE−/− mice accelerated atherosclerotic plaque formation, and then the gut microbiota and metabolites were detected using metagenomics and untargeted metabolomics. Our results showed that PSRC1 deficiency enriched trimethylamine (TMA)-producing bacteria and functional potential for TMA synthesis and accordingly enhanced plasma betaine and TMAO production. Furthermore, PSRC1 deficiency resulted in a proinflammatory colonic phenotype that was significantly associated with the dysregulated bacteria. Unexpectedly, hepatic RNA-seq indicated upregulated flavin monooxygenase 3 (FMO3) expression following PSRC1 knockout. Mechanistically, PSRC1 overexpression inhibited FMO3 expression in vitro, while an ERα inhibitor rescued the downregulation. Consistently, PSRC1-knockout mice exhibited higher plasma TMAO levels with a choline-supplemented diet, which was gut microbiota dependent, as evidenced by antibiotic treatment. To investigate the role of dysbiosis induced by PSRC1 deletion in atherogenesis, apoE−/− mice were transplanted with the fecal microbiota from either apoE−/− or PSRC1−/−apoE−/− donor mice. Mice that received PSRC1-knockout mouse feces showed an elevation in TMAO levels, as well as plaque lipid deposition and macrophage accumulation, which were accompanied by increased plasma lipid levels and impaired hepatic cholesterol transport. Overall, we identified PSRC1 as an atherosclerosis-protective factor, at least in part, attributable to its regulation of TMAO generation via a multistep pathway. Thus, PSRC1 holds great potential for manipulating the gut microbiome and alleviating atherosclerosis.
Schwann cells in the subcutaneous adipose tissue have neurogenic potential and can be used for regenerative therapies
Authors: Rhian Stavely, Ryo Hotta, Nicole Picard, Ahmed A. Rahman, Weikang Pan, Sukhada Bhave, Meredith Omer, Wing Lam N. Ho, Richard A. Guyer, Allan M. Goldstein
Journal: Science Translational Medicine (2022)

Stem cell therapies for nervous system disorders are hindered by a lack of accessible autologous sources of neural stem cells (NSCs). In this study, neural crest–derived Schwann cells are found to populate nerve fiber bundles (NFBs) residing in mouse and human subcutaneous adipose tissue (SAT). NFBs containing Schwann cells were harvested from mouse and human SAT and cultured in vitro. During in vitro culture, SAT-derived Schwann cells remodeled NFBs to form neurospheres and exhibited neurogenic differentiation potential. Transcriptional profiling determined that the acquisition of these NSC properties can be attributed to dedifferentiation processes in cultured Schwann cells. The emerging population of cells were termed SAT-NSCs because of their considerably distinct gene expression profile, cell markers, and differentiation potential compared to endogenous Schwann cells existing in vivo. SAT-NSCs successfully engrafted to the gastrointestinal tract of mice, migrated longitudinally and circumferentially within the muscularis, differentiated into neurons and glia, and exhibited neurochemical coding and calcium signaling properties consistent with an enteric neuronal phenotype. These cells rescued functional deficits associated with colonic aganglionosis and gastroparesis, indicating their therapeutic potential as a cell therapy for gastrointestinal dysmotility. SAT can be harvested easily and offers unprecedented accessibility for the derivation of autologous NSCs from adult tissues. Evidence from this study indicates that SAT-NSCs are not derived from mesenchymal stem cells and instead originate from Schwann cells within NFBs. Our data describe efficient isolation procedures for mouse and human SAT-NSCs and suggest that these cells have potential for therapeutic applications in gastrointestinal motility disorders.
Synthetic antigenic determinants of clavulanic acid induce dendritic cell maturation and specific T cell proliferation in patients with immediate hypersensitivity reactions
Authors: Ruben Fernandez‐Santamaria, Gador Bogas, Maria Isabel Montañez, Adriana Ariza, Maria Salas, Jose Antonio Cespedes, Marina Labella, Juan Luis Paris, Natalia Perez‐Sanchez, Ezequiel Perez‐Inestrosa, Yolanda Vida, Tahia D. Fernandez, Cristobalina Mayorga, Maria Jose Torres
Journal: Allergy (2022)

Immediate drug hypersensitivity reactions (IDHRs) to clavulanic acid (CLV) have increased in the last decades due to a higher consumption alongside amoxicillin (AX). Due to its chemical instability, diagnostic procedures to evaluate IDHRs to CLV are difficult, and current in vitro assays do not have an optimal sensitivity. The inclusion of the specific metabolites after CLV degradation, which are efficiently recognised by the immune system, could help to improve sensitivity of in vitro tests.Recognition by dendritic cells (DCs) of CLV and the synthetic analogues of two of its hypothesised antigenic determinants (ADs) was evaluated by flow cytometry in 27 allergic patients (AP) and healthy controls (HC). Their ability to trigger the proliferation of T cells was also analysed by flow cytometry.The inclusion of synthetic analogues of CLV ADs, significantly increased the expression of maturation markers on DCs from AP compared to HC. A different recognition pattern could be observed with each AD, and, therefore, the inclusion of both ADs achieves an improved sensitivity. The addition of synthetic ADs analogues increased the proliferative response of CD4+ Th2 compared to the addition of native CLV. The combination of results from both ADs increased the sensitivity of proliferative assays from 19% to 65% with a specificity higher than 90%.Synthetic ADs from CLV are efficiently recognised by DCs with ability to activate CD4+ Th2 cells from AP. The combination of analogues from both ADs, significantly increased the sensitivity of DC maturation and T-cell proliferation compared to native CLV.
Table of Contents
Authors: Rebekah Rittberg, Ninan Abraham, Alessio Cortellini, Francesco Facchinetti, Lisa Derosa, David Pinato, Nikolaj Frost, Frank Griesinger, Hans Hoffmann, Florian Länger, Ursula Nestle, Wolfgang Schütte, Jürgen Wolf, Martin Reck, Stefano Scalera, Marco Mazzotta, Clelia Cortile, Eriseld Krasniqi, Ruggero De Maria, Federico Cappuzzo, Gennaro Ciliberto, Marcello Maugeri-Saccà, Ashley Hopkins, Sarah Badaoui, Ganessan Kichenadasse, Christos Karapetis, Ross Mckinnon, Andrew Rowland, Michael Sorich, Caroline Mccoach, Christian Rolfo, Alexander Drilon, Mario Lacouture, Benjamin Besse, Koichi Goto, Viola Zhu, Daniel Tan, Stephanie Farajian, Laura Potter, Jennifer Kherani, Victoria Soldatenkova, Elizabeth Olek, Catherine Muehlenbein, Keunchil Park
Journal: Journal of Thoracic Oncology (2022)
Infantile Mitochondrial Cardiomyopathy – A Case Report Presenting a Rare Cause for Hypertrophic Cardiomyopathy
Authors: Fiona Becker-Dettling, Robert Dalla-Pozza, Adelheid Kley, Esther M. Maier, Stephanie Regenauer-Vandewiele
Journal: Clinical Cardiology and Cardiovascular Interventions (2022)

Infantile hypertrophic cardiomyopathy (HCM) comprises a group of rare and heterogeneous diseases and is the second most common cause of cardiomyopathy in childhood and adolescents. In general, the muscular hypertrophy results in histological and functional disorder. The prognosis depends on the underlying aetiology. However, HCM represents a high risk of mortality especially in neonates. Rarely, mitochondrial dysfunction is accountable for HCM. Here we describe a case of a rapidly progressive infantile HCM caused by complex V deficiency due to overlapping mt mutations in ATP6 and ATP8 with lethal course in a premature neonate suggesting early genetic testing in risk groups to clarify differential diagnosis, and determine thereby prognosis and rational therapy options.